. Interactions of leukocytes with platelets and endothelium may be fundamental events that link the hemostatic and inflammatory responses to tissue injury. GMP-140, a membrane glycoprotein of platelet and endothelial cell secretory granules, is rapidly redistributed to the plasma membrane during cellular activation, where it serves as an inducible receptor for neutrophils and monocytes. GMP-140, along with ELAM-1 and the Mel 14/Leu 8 antigen, comprise the selectin family of cell surface molecules that mediate interactions of leukocytes with other blood or vascular cells. Each selectin contains an N-terminal domain homologous to Ca2+-dependent lectins, followed by an EGF-like domain, a variable number of consensus repeats similar to those in complement-binding proteins, a transmembrane domain, and a short cytoplasmic tail. The lectin and EGF domains of the selectins show particularly striking sequence homology. We have found that the lectin domain of GMP-140 is involved in neutrophil recognition and that this interaction is modulated by at least two divalent-cations binding sites. We postulate that; (1) the EGF-like domain enhances the binding affinity and specificity of the lectin domain for leukocytes; (2) separate functionally relevant binding sites for divalent cations reside on both the lectin and EGF domains, and (3) oligosaccharides comprise part of the receptor on leukocytes that interacts with the lectin domain of GMP-140. We propose to; (1) correlate divalent cation-dependent conformational changes in GMP-140 with ability of the protein to bind to neutrophils; (2) Perform detailed structure-function analyses of the individually expressed lectin and EGF-like domains and characterize potential interactions between the domains; (3) Isolate and characterize the leukocyte receptor for GMP-140. These studies should advance our understanding of the molecular basis for interactions of leukocytes with platelets and endothelium and may provide one of the first examples of a biologically significant, highly specific recognition event between a cell surface lectin and a cell surface oligosaccharide.